Xenografting

At the in vivo assay level, the classic ip-ip (iateraperitoneal) in vivo model has been replaced as a selection criteria for advancement of new dmg candidates to clinical trial. More stringent alternative models iaclude subcutaneous or subrenal capsule implantation of tumor followed by iatravenous dmg dosiag (7) and the human tumor xenograft models ia aude mice (8). 

DABROSiN c, CHEN J, WANG L and THOMPSON L u (2002) Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in human breast cancer xenografts. Cancer Lett. 185 (1) 31-7. 

In vivo studies were carried on the aziridinated cyclopent[Z ]indole quinone out before it was discovered that the aziridinyl ring did not participate in DNA alkylation. The results in Fig. 7.22 for the B16 melanoma syngraft model reveal that there was substantial reduction of tumor mass at 3 mg/kg. However, toxicity (animal deaths) became apparent at 5 mg/kg. On the other hand, human lung cancer xenografts in SCID (severe combined immunodeficient) mice were reduced to 50% mass with 3x1 mg/kg doses without any animal deaths. 

Berin MC, Eckmann L, Broide DH, Kagnoff MF. Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts. Am J Respir Cell Mol Biol 2001 24(4) 382-389. 

FIGURE 4.12 Experimental 2D-PAGE map of a neuroblastoma xenograft implanted in mice. The circles indicate the spots identified by MS analysis. Reproduced from Campostrini et al. (2005) with permission from Wiley-VCH Verlag GmbH. 

Miller, F. R. (2000). Xenograft models of premalignant human breast disease. J. Mammary Gland Biol. 5, 379-391. 

Chen X, Conti PS, Moats RA (2004) In vivo near-infrared fluorescence imaging of integrin av(33 in brain tumor xenografts. Cancer Res 64 8009-8014... 

Kawato Y, Furuta T, Aonuma M et al. Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. Cancer Chemother Pharmacol 1991 28 192-198. 

ABT-888 (22) shows limited activity as monotherapy however, it strongly potentiates the activity of multiple DNA-damaging agents in preclinical models [39]. ABT-888 potentiated TMZ in a glioma model in a dose-dependent manner, with maximal efficacy achieved at 50 mg/ kg, which reduced tumor volume by 63%, 44% better than TMZ alone. In the MX-1 breast xenograft model, ABT-888, at 5 mg/ kg/ day in combination with cisplatin, caused sustained regressions in 8/9 mice compared to 3/9 for cisplatin monotherapy. 

ATM-deficient cell lines were found to be sensitive to olaparib [53]. In xenograft studies using ATM-deficient Granta-519 cells, olaparib was shown to decrease tumor growth and prolong overall survival by 42%. 

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